Leukemias arise when stem/hematopoietic progenitor cells acquire mutations that enable them to escape control mechanisms regulating proliferation and which disable the cells' ability to differentiate. Two subtypes exist which are defined by the cells involved: lymphoid cells (Acute Lymphoid Leukemia; ALL) or myeloid cells (Acute Myeloid Leukemia; AML). Despite many years of research, a comprehensive understanding of all of the genetic causes of leukemia has not yet been generated. One class of leukemias of clinical interest are those which involve translocations of the mixed-lineage leukemia (MLL) gene. MLL was cloned in 1992 from the t(11;19) (11q23;19p13) chromosomal translocation that is recurrently associated with both myelomonocytic AML and ALL. MLL is a large gene (˜90 kb) and its 11.9 kb mRNA encodes a protein of 3968 amino acids with a very complex structure. MLL is a key regulator of hematopoiesis and is also important in embryogenesis for its positive regulation of homeobox HOX gene expression. To date, more than 50 different translocations involving MLL have been identified in acute human leukemias. The most common MLL fusion partners in AMLs are AF9 t(9:11), AF10, AF6 and ELL. MLL fusion genes are also identified in more than 30% of therapy-related leukemias, typically after topoisomerase II inhibitors or alkylating agent therapies. Generally, 11q23 translocations confer a poor prognosis similar to unfavorable prognostic subgroups of ALL and AML.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.